Peter Besmer, PhD

Receptor Tyrosine Kinase Signaling In Vitro and In Vivo in Mice

The objective of our research is to investigate the mechanisms by which receptor tyrosine kinases produce cellular responses in vitro in cell systems and in vivo in mice. As a model, the Kit receptor tyrosine kinase and its agonist, the membrane growth factor Kit-ligand (KL), are being studied. Phenotypes of mice with mutations in the genes for the Kit receptor tyrosine kinase and its ligand KL imply roles in gametogenesis, hematopoiesis, and melanogenesis. Based on mutant phenotypes in distinctive cell compartments during embryogenesis and in the postnatal animal, the cellular responses mediated by the Kit receptor are quite diverse and include cell proliferation, cell survival, cell adhesion, cell migration, secretion of mediators, cell differentiation, and other postmitotic functions.

The goal of our research is to elucidate the mechanisms by which the Kit receptor generates these cellular responses in distinct cell populations in vivo, with an emphasis on Kit functions in hematopoiesis and gametogenesis. We are investigating 3 different aspects of Kit signaling/function:

• the roles of soluble and membrane KL in vivo and the mechanism of the formation of soluble KL in vivo and in vitro;
• the roles of distinct signaling pathways activated by Kit in generating cellular responses in vivo and in vitro; and
• the mechanism by which Kit expression is regulated in a cell type-specific manner.

The methodologies being used in these investigations include molecular biology, cell biology, and transgenic mouse approaches (transgenic, knock-out, and knock-in methodologies).